Human papillomaviruses (HPVs) cause cutaneous, genital, and cervical warts. A subset of the HPVs are associated with a high risk for malignant conversion. The applicant's laboratory has identified potential new anti-papillomaviral compounds that have utility against a wide range of HPVs. The goal is to further evaluate and refine these antivirals and identify additional targets for antiviral drug design. Papillomaviruses encode about ten proteins. The E2 protein is a particularly interesting target for the development of antiviral therapy, because it coordinates viral transcription and is required for viral DNA replication. In this application, the principal investigator and colleagues propose to study domains of the E2 protein. The 3D structures of the different E2 domains will be deduced by NMR analyses. These determinations will guide antiviral design. Substantial progress has been obtained in the identification of an E2 specific antiviral. In addition, initial studies demonstrate the feasibility of obtaining NMR deduced 3D structures of E2 domains. Thus the goal of the proposed research is to combine structural with functional analyses of E2 to rationally design specific antipapillomaviral drugs.